Renal Pathophysiology



Studies have documented the shedding of proximal brush border membranes and viable epithelial cells into the urine. With ischemic injury, abnormalities of the cytoskeleton have been demonstrated that result in the translocation of the Na + -K + -ATPase from the basolateral to the apical membrane. This loss of vectorial sodium transport could explain the decrease in tubular sodium reab sorption that occurs in this condition. Hypoxia-induced activation of cysteine proteases such as calpain may play a role in the Na + -K + -ATPase translocation. In addition, the accumulation of cellular debris results in intratubular obstruc tion and the finding of dilated tubules on renal biopsy. The resulting elevation in intraluminal tubular pressure can disrupt epithelial cell tight junctions and integrin-mediated adhesion causing backleak of glomerular ultrafiltrate into the circulation. The decrease in proximal tubule sodium chloride reabsorption that results from these processes will lead to increased delivery to the macula densa and activate tubuloglomerular feedback to reduce GFR. Because the af ferent arteriole is vasoconstricted with ischemic injury, this may be sufficient to explain the very low GFR. Inflammation/Immune Response Ischemia-reperfusion injury induces the release of inflammatory cytokines including tumor necrosis factor- α (TNF α ); monocyte chemotactic protein-1 (MCP-1); transforming growth factor- β (TGF β ); interleukin (IL)-6, 8, 18; and activation of Toll-like receptors, resulting in increased neutrophil adhesion and activation of monocytes/macrophages dendritic cells and T lympho cytes. The complement pathway is also activated, and numerous signals con tribute to these responses, including reactive oxygen species and nitric oxide (NO). Inducible nitric oxide synthase (iNOS) is stimulated with ischemia leading to increased NO levels, and the scavenging of NO by oxygen radicals produces peroxynitrite that contributes to tubular damage. In some nephrons, the cellular injury is severe enough to impair sodium reabsorption but not severe enough to induce backleak. How might reduced sodium chloride reabsorption in the proximal tubule and loop of Henle contribute to the decline in GFR in ATN? Consider the mechanisms by which the GFR is normally regulated. Treatment and Prevention Although it is often possible to identify patients at risk for developing ATN and major advances in understanding the pathogenesis have been achieved, effective therapeutic strategies remain elusive. Supportive care with dialysis and correction of electrolyte and metabolic disturbances remain the main stay of therapy. Numerous potential strategies have been tried but have not been found to be effective in patients with ischemic ATN (although several have demonstrated efficacy in animal models). These unsuccessful strategies 5

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